In alignment with Beta Cell Biology Consortium (BCBC) research priorities, we have assembled a strong multidisciplinary team of established investigators to identify epigenetic and genetic programs underlying human pancreatic (-cell development, growth, maturation, function, and fate control. Growth of knowledge about human pancreas and islet developmental biology will accelerate creation of cell therapies for diabetes mellitus, and we propose studies here with an experimental focus on fetal, juvenile and adult human (-cells. For these studies, our team has created and shared new reagents and experimental methods, including human and mouse genetic tools, procurement of human islets with ongoing physiological (-cell proliferation, cell purification strategies, and genome-scale molecular profiling. We will use these and other innovative resources to investigate promising mechanisms for generating functional (-cells, including derivation from multipotent human stem cells, cell reprogramming, and expansion of existing (-cells. In Project 1, we will combine the power of advanced mouse genetics, cell purification, and genomics to elucidate genetic and epigenetic mechanisms controlling development and fates of islet (-cells and other pancreatic cell subsets. These studies should establish genetic and epigenetic foundations for directing controlled cell reprogramming to regenerate (-cells. In Project 2, we will investigate the genetic and epigenetic basis for human pancreatic and islet cell development and maturation, by purifying defined cell subsets from fetal and juvenile human pancreata and applying 'ultrahigh'throughput genomic-scale studies of gene expression and chromatin. In Project 3, we will create new human induced pluripotent stem (iPS) cell lines harboring mutations in genes encoding crucial regulators of pancreatic (-cell development, maturation, and function. These iPS cell lines will provide a unique experimental platform to reveal fundamental genetic and epigenetic mechanisms controlling human islet (-cell development, fate and function. Data sharing, hypotheses, and collaborations fostered in the BCBC through our studies should speed progress toward meeting the BCBC mandate to discover cellular therapies for diabetes mellitus. PUBLIC HEALTH RELEVANCE: In alignment with stated Beta Cell Biology Consortium priorities, our team of investigators proposes to identify the molecular programs underlying human pancreatic islet development, growth, maturation and function to accelerate progress toward cell therapies for diabetes mellitus. We will investigate promising mechanisms for generating functional beta cells, including derivation from multipotent human stem cells, reprogramming of other pancreatic cells, and expansion of existing beta cells.